Fluid Resuscitation in Sepsis: New Perspectives on an Old Concept

Amanda Decimo, RN, MSN, MPH

Experts on the topic of sepsis, Andrew Shaw, MD, Ashish K. Khanna, MD, and Judith Hellman, MD, provided the latest research on sepsis resuscitation in the session, “Resuscitation in Sepsis and Septic Shock,” held on Sunday, March 20 at the IARS 2022 Annual Meeting. Their presentations stressed the importance of fluid management, as virtually all hospitalized patients require IV fluid.  

The first presenter Andrew Shaw, MD, Chairman, Department of Intensive Care and Resuscitation at the Cleveland Clinic, presented “Choice of Fluids for Resuscitation: Is BEF your BFF?” He briefly reviewed the past 100 years of research, including his own, all of which supported that buffered or balanced electrolyte fluid (BEF), such as Plasma-Lyte, yield better patient outcomes during fluid resuscitation than normal saline.

Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte (Ann Surg 2012) and Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis (Crit Care Med 2014), two of Dr. Shaw’s studies, both demonstrated that saline, compared with buffered solutions, results in greater adverse outcomes and mortality in surgical and septic patients.

Dr. Shaw then reviewed the SMART and SALT-ED trials (NEJM 2018) that randomized large groups of ICU and emergency room patients to either saline or balanced salt solutions. Major adverse kidney events were used as study outcomes. The saline groups all possessed significantly higher outcomes of death, new dialysis, and persistent renal dysfunction.

However, two recent studies, published in the past year, weighed in on the saline versus salt balances debate and seemed to contradict the majority of fluid resuscitation research. The BaSICS study (JAMA 2021) showed no difference in 90-day mortality between subgroups. Traumatic brain injury (TBI) patients actually had improved outcomes with saline, due to fluid tonicity. The PLUS study (NEJM 2022) showed no difference between the two fluid groups. Why the contradiction in these results? Dr. Shaw suggested that the volumes used for resuscitation in these two studies were low (4L over 6 days) and crossover occurred, as patient subgroups were exposed to both saline and balanced salt solution treatment, clouding study outcomes.

Dr. Shaw wrapped up his presentation with a new, landmark meta-analysis (Hammond et al, NEJM 2022), that synthesizes the large body of available research and found that overall there is a 90% probability that BES reduces mortality in ICU patients. Dr. Shaw concluded that BEF is your BFF, with the caveat that for TBI resuscitation outcomes are better with normal saline.

Ashish K. Khanna, MD, Associate Professor and Vice-Chair for Research, Department of Anesthesiology, Section on Critical Care Medicine at Wake Forest Baptist Medical Center, discussed vasopressors and fluids as a component of septic shock management.

Traditional fluid resuscitation guidelines in septic shock suggest fluid first; then, if unable to maintain MAP ≥65 proceed with vasopressors. However, the challenge is how the tank is filled and minimizing how long patients remain hypotensive.  

Current sepsis resuscitation guidelines (Evans et al 2021) offered less clear recommendations for the use of fluid before vasopressors. No clear recommendation is given for restricted versus liberal crystalloid resuscitation in first 24 hours after initial resuscitation. In fact, The Surviving Sepsis Research Group declared research on the appropriate ratio of fluid to pressures a high priority. Dr. Khanna proposed that if vasopressors are started earlier, the tank may be smaller and require less fluid.

However, the Volume Chasers study (Soc of Crit Care Medicine 2019) found the best dosing strategy was to start vasopressors early, then titrate down during resuscitation. Furthermore, best outcomes occurred when interventions included personalized clinician assessments of hemodynamics measures to tailor this process. This improved survival.

Does a good blood pressure improve microcirculation? Not necessarily, as tissue edema and sluggish blood flow can occur with large amount of pressors, Dr. Khanna explained. He recommended early multimodal vasopressor and fluid use, biomarker guided therapy (renin), and the use of adjuncts to manage sepsis resuscitation better.

The next presenter Judith Hellman, MD, Professor and Vice Chair of Research and Research Lab Director, at University of California, San Francisco, leads a research program focused on basic and translational research on sepsis and other forms of inflammation-driven acute organ failure (“Inflammatory Critical Illness”). In her lecture, “Endothelial and Microvascular Dysfunction in Sepsis,” she provided a closer look under the microscope. She explained that endothelial cells are nonclassical immune cells that can be important targets for sepsis-based therapies. These cells express innate immune receptors and activate inflammatory pathways that result in increased vascular permeability and coagulopathy.

Dr. Hellman explained that endothelial cells can be challenging to study during sepsis as they are hard to assess in real time. Studies of mice, show that their endothelial cell response is sluggish, which differs from humans. Even responses from different human endothelial cells vary widely, she extrapolated. This creates challenges for research.

Endothelial cell targeting and immunomodulation hold a great potential for treatment of septic patients, according to Dr. Hellman. Immunomodulation is the process of changing the host’s immune system caused by intrinsic or extrinsic factors that activate or suppress the immune system. In Dr. Hellman’s lab, a revealing study (Joffre et al, CCM 2021) discovered that epinephrine and norepinephrine completely reversed endothelial permeability induced by LPS via beta-adrenergic receptors. These exciting discoveries shed light on potential endothelial targets for future sepsis therapies that may reduce vascular leak and coagulopathy.